Isabel Reinecke (1), Birte Hofmann (2), Emir Mesic (3), Henk-Jan Drenth (3), Dirk Garmann (4)
(1) Clinical Pharmacometrics, Bayer AB, Solna, Sweden, on behalf of Bayer AG, Berlin, Germany; (2) Clinical Pharmacokinetics, Bayer AG, Berlin, Germany; (3) LAP&P Consultants BV, Leiden, The Netherlands; (4) Clinical Pharmacometrics, Bayer AG, Wuppertal, Germany
Introduction: Women can choose among a number of contraceptives and administration routes containing the progestin levonorgestrel. This hormone is used as a component in contraceptives because of its influence on at least 2 mechanisms in preventing pregnancy: ovulation inhibition and thickening of the cervical mucus. A direct comparison of levonorgestrel daily doses and exposure of these different products has not been made until recently [1]. Levonorgestrel-containing contraceptives administered orally or as an implant act mainly via their systemic levonorgestrel exposure, whereas levonorgestrel administered via an intrauterine system (IUS) is released directly into the uterine cavity, resulting in lower systemic levonorgestrel concentrations. All levonorgestrel-containing contraceptives included in this analysis are known to be safe and highly effective, despite the fact that they differ in administration route, daily levonorgestrel dose and systemic exposure. However, a comparison of daily dose and exposure would support decision making between products by health care providers and by the women themselves.
Objectives:
- Compare typical levonorgestrel exposure for 3 IUSs, 2 oral contraceptives, and an implant, by simulating the exposure for the same treatment duration with an integrated population PK (popPK) model.
- Compare absolute bioavailability and daily levonorgestrel doses by calculating in vivo release rates for the IUSs and implant based on the integrated popPK model.
Methods: For this analysis, data from 10 clinical pharmacology studies in healthy premenopausal women (n=3424) with 6 levonorgestrel-containing contraceptives, including iv data, were integrated: 3 intrauterine systems (IUSs; levonorgestrel [LNG]-IUS 20 [Mirena®], LNG-IUS 12 [Kyleena®], and LNG-IUS 8 [Jaydess®/Skyla®]); 2 oral contraceptives (the progestin-only pill [Microlut®/Norgeston®] and the combined oral contraceptive [Miranova®]); and a subdermal implant (Jadelle®). The integrated population PK analysis was performed by means of a nonlinear mixed-effects approach using NONMEM® software (Version 7.2.0). Simulations were performed using R software (version 3.2.0 or higher).
Results: The estimated released daily dose of levonorgestrel into the uterine cavity for LNG-IUS 20 decreased over the 5 years of period-of-use from 21.7 µg after 24 days to 10.7 µg after 5 years, for LNG-IUS 12 from 15.4 µg after 24 days to 7.59 µg after 5 years, and for LNG-IUS 8 (3 years period-of-use) from 13.4 µg after 24 days to 5.51 µg after 3 years. The estimated absolute bioavailability was close to 100% for all 3 IUSs. The estimated daily dose of the implant (5 years period-of-use) decreased from 53.0 µg after 24 days to 32.8 µg after 5 years. The absolute bioavailability was estimated to be 66.0%. Compared to that, the daily dose of the combined oral contraceptive was 100 µg, in combination with 20 µg ethinylestradiol (28-day cycle, i.e. 21 days on/7 days off), and of the progestin-only pill 30 µg (absolute bioavailability estimated at approximately 80% for both oral contraceptives). Thus, the highest daily dose is provided by the combined oral contraceptive, followed, in decreasing order, by the progestin-only pill and the implant (both similar daily doses), and the IUSs LNG-IUS 20, LNG-IUS 12, and LNG-IUS 8. This is in line with the comparison of the estimated levonorgestrel exposure. The geometric mean of the average total levonorgestrel concentration at steady-state of the combined oral contraceptive was estimated to be 1676 ng/L whereas the geometric mean of the total levonorgestrel concentration of the LNG-IUS 8, the IUS with the lowest daily dose, decreased from 127 ng/L after 24 days to 58.1 ng/L after 3 years, which is only approximately 8 % and 3 %, respectively, of the average serum concentration of the combined oral contraceptive.
Conclusions: The integrated popPK analysis allowed a valid comparison of daily levonorgestrel doses and systemic exposure for 6 levonorgestrel-containing contraceptives which may support decision making between products by health care providers and by the women themselves. The analysis revealed that the combined oral contraceptive provided the highest daily levonorgestrel dose and led to the highest levonorgestrel exposure, whereas the IUSs, in particular LNG-IUS 8, provided the lowest daily levonorgestrel dose and led to the lowest systemic levonorgestrel exposure.
References:
[1] Reinecke I, Hofmann B, Mesic E, Drenth HJ, Garmann D. An Integrated Population Pharmacokinetic Analysis to Characterize Levonorgestrel Pharmacokinetics After Different Administration Routes. The Journal of Clinical Pharmacology (2018), 58:12, 1639-1654.
Reference: PAGE 28 (2019) Abstr 8983 [www.page-meeting.org/?abstract=8983]
Poster: Drug/Disease Modelling - Other Topics